Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, ON, Canada.
Can J Cardiol. 2013 Jul;29(7 Suppl):S24-33. doi: 10.1016/j.cjca.2013.04.002.
Warfarin has been the mainstay oral anticoagulant (OAC) medication prescribed for stroke prevention in atrial fibrillation (AF) patients. However, warfarin therapy is challenging because of marked interindividual variability in dose and response, requiring frequent monitoring and dose titration. These limitations have prompted the clinical development of new OACs (NOACs) that directly target the coagulation cascade with rapid onset/offset of action, lower risk for drug-drug interactions, and more predictable response. Recently, NOACs dabigatran (direct thrombin inhibitor), and rivaroxaban and apixaban (factor Xa [FXa] inhibitors) have gained regulatory approval as alternative therapies to warfarin. Though the anticoagulation efficacy of these NOACs has been characterized, differences in their pharmacokinetic and pharmacodynamic profiles have become a significant consideration in terms of drug selection and dosing. In this review, we outline key pharmacokinetic and pharmacodynamic features of each compound and provide guidance on selection and dosing of the 3 NOACs relative to warfarin when considering OAC therapy for AF patients. Importantly, we show that by better understanding the effect of clinical variables such as age, renal function, dosing interval, and drug metabolism (CYP3A4) and transport (P-glycoprotein), we might be able to better predict the risk for sub- and supratherapeutic anticoagulation response and individualize OAC selection and dosing.
华法林一直是心房颤动 (AF) 患者预防中风的主要口服抗凝药物 (OAC)。然而，由于剂量和反应的个体差异明显，华法林治疗具有挑战性，需要频繁监测和剂量调整。这些局限性促使开发了新的 OAC（NOAC），这些药物直接靶向凝血级联反应，具有快速起效/消除作用、药物相互作用风险较低以及更可预测的反应。最近，达比加群（直接凝血酶抑制剂）、利伐沙班和阿哌沙班（Xa 因子 [FXa] 抑制剂）已获得监管部门批准，作为华法林的替代疗法。尽管这些 NOAC 的抗凝疗效已得到描述，但在药物选择和剂量方面，它们在药代动力学和药效学特征方面的差异已成为一个重要的考虑因素。在这篇综述中，我们概述了每种化合物的关键药代动力学和药效学特征，并就 AF 患者的 OAC 治疗中相对于华法林选择和剂量方面提供了指导。重要的是，我们表明，通过更好地了解年龄、肾功能、给药间隔以及药物代谢（CYP3A4）和转运（P-糖蛋白）等临床变量的影响，我们可能能够更好地预测亚治疗和超治疗抗凝反应的风险，并实现个体化的 OAC 选择和剂量调整。
